Healing a broken heart

How a vitamin A metabolite could help myocardial infarction patients by modulating blood stem cell activity

April 02, 2025

Graphical Abstract - A vitamin A metabolite could protect heart function by specifically controlling the immune response and offer a promising long-term therapy for heart attack patients. — Myocardial infarction affects bone marrow cells and a possible treatment. The left panel explains that after a heart… [more]
Myocardial infarction affects bone marrow cells and a possible treatment. The left panel explains that after a heart attack, hematopoectic stem cells (HSCs) in the bone marrow decrease in number and function, while immune cells become more active, leading to long-term changes. The right panel depicts a potential intervention using 4-oxo-RA, a vitamin a metabolite, to reduce HSC activation, lower myeloid output, decrease emergency hematopoiesis and cardiac infiltration, ultimately promoting cardiac repair.
[less]

© MPI of Immunobiology and Epigenetics/ Cabezas-Wallscheid

Myocardial infarction affects bone marrow cells and a possible treatment. The left panel explains that after a heart attack, hematopoectic stem cells (HSCs) in the bone marrow decrease in number and function, while immune cells become more active, leading to long-term changes. The right panel depicts a potential intervention using 4-oxo-RA, a vitamin a metabolite, to reduce HSC activation, lower myeloid output, decrease emergency hematopoiesis and cardiac infiltration, ultimately promoting cardiac repair.

© MPI of Immunobiology and Epigenetics/ Cabezas-Wallscheid

To the point

After a heart attack: The excessive production of immune cells can trigger inflammation, potentially leading to heart scarring and, over time, heart failure.
A possible solution: A vitamin metabolite called 4-oxo-RA shows promise as a targeted therapy by modulating bone marrow stem cells to reduce excessive inflammation.
Targeted treatment: By addressing the root of the immune response, 4-oxo-RA may improve long-term heart function.

After a heart attack, clinically known as myocardial infarction, the immune system scales up the production of inflammatory immune cells. While these cells aid in wound healing, an excessive production, which is common in heart attack patients, can lead to harmful inflammation, scarring of the heart, and long-term heart failure.

In a preclinical study, the teams of Nina Cabezas-Wallscheid and Timo Heidt discovered that the vitamin A metabolite »4-oxo-retinoic acid« can regulate excessive immune response by keeping hematopoietic stem cells in the bone marrow inactive. Since these stem cells give rise to inflammatory immune cells, reducing their activity leads to fewer inflammatory cells being produced. This, in turn, decreases cardiac inflammation, helps prevent heart scarring and ultimately preserves heart function.

Analyzing human cells from myocardial infarction patients

The team collected bone marrow samples from the sternum of more than 100 infarction patients and conducted extensive single-cell transcriptome analyses. Using this method, researchers can identify which genes are active in a cell and assess the status of the stem cells in the samples. They discovered that a heart attack significantly alters bone marrow hematopoietic stem cell activity, potentially leading to the production of inflammatory blood cells that may, over time, damage heart tissue.

Their findings showed that treatment with 4-oxo-retinoic acid not only reduced the overproduction of immune cells but also significantly improved long-term heart function. The study found that 4-oxo-retinoic acid acts specifically on hematopoietic stem cells in the bone marrow without causing adverse effects on heart tissue, presenting potential advantages over other treatments.

This targeted regulation of bone marrow activity could be a promising strategy to support healing after a heart attack and reduce the risk of future complications. Co-first author Jasmin Rettkowski says: “It’s fascinating how a single metabolite can influence stem cells so profoundly. Our study highlights the underestimated role of bone marrow stem cells in post-heart attack inflammation and identifies 4-oxo-retinoic acid as a promising therapeutic tool.”

A new therapeutic treatment strategy to protect heart function

The findings open new possibilities for developing innovative therapies to improve post-heart attack recovery. “Rather than broadly suppressing inflammation, our study suggests specifically modulating hematopoietic stem cell activity to reduce the production of inflammatory cells. This approach could lead to more effective treatments with fewer side effects”, says co-first author Mari Carmen Romero-Mulero.

The research team is actively working on bringing this approach into the clinic and has already taken initial steps toward clinical trials. “At ETH Zurich, we will address if our discovery is also applicable in humans. Of course, further studies are needed to evaluate the safety and efficacy of 4-oxo-retinoic acid in patients” says Nina Cabezas-Wallscheid who is currently relocating her lab from Freiburg to Zurich.

NCW/MR